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Princeton University researchers discovered a new compound that works like a 'poisoned arrow' antibiotic which can destroy bacteria and at the same time remains immune to antibiotic resistance. The compound SCH-79797 has the ability to penetrate bacterial walls while destroying cell folate.

Bacterial infections in the study were labeled as Gram-positive and Gram-negative, bacteria with an outer layer of armor that dismisses most antibiotics. Zemer Gitai, an Edwin Grant Conklin Professor of Biology from the university said that 'This is the first antibiotic that can target Gram-positive and Gram-negatives without resistance.'

As scientists, what they're excited about the most, Gitai shared, was discovering something new about the antibiotic works - 'attacking via two different mechanisms within one molecule - that we are hoping is generalizable, leading to better antibiotics - and new types of antibiotics - in the future.'

Generally, the greatest weakness of antibiotics is the bacteria's ability to evolve and quickly resist medicine. The team was unable to generate any form of resistance against SCH-79797, naming the compound's derivatives 'Irresistin.'

James Martin, a Ph.D. graduate who worked with the compound said that his 'first challenge was convincing the lab that it was true,' because the antibiotic is effective against diseases while being immune to resistance and safe for humans. It's even better than rubbing alcohol or bleach which are fatal for bacteria and human cells alike.

However, antibiotic research means that the team included breeding multiple generations of the compound until bacteria evolves to a state of resistance, so they can reverse-engineer the molecule. With the new compound being irresistible, there is nothing to reverse-engineer from. In trying to prove that the compound is in fact irresistible and figuring out how it works, Martin attempted several ways to trigger the bacteria to evolve from multiple antibiotic doses and exposure to resistant bacterial species like gonorrhea.

'Poisoned Arrow'

After years of finding no resistance to the antibiotic, the team eventually discovered that the single-molecule has two distinct mechanisms, like a 'poisoned arrow.' Benjamin Bratton, a molecular biology researcher and lecturer from the Lewis Sigler Institute for Integrative Genomics said that 'The arrow has to be sharp to get the poison in, but the poison has to kill on its own, too.'

The arrow penetrates the thick armor, or outer membrane of the Gram-negative bacteria while poisoning folate, a building block of DNA and RNA - two mechanisms operating synergistically. Bratton described it as, 'If you just take those two halves - there are commercially available drugs that can attack either of those two pathways - and you just dump them into the same pot, that doesn't kill as effectively as our molecule, which has them joined together on the same body,'

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Antibiotic Development

One problem in their experiments was that the original antibiotic killed both human and bacterial cells at a similar level, meaning that converted into medicine, it could possibly kill the patient before killing the infection. However, the derivative Irresistin-16 fixed that issue. Being almost 1000 times more potent against bacterial cells than human cells, the promising antibiotic was confirmed to cure 16 mice infected with gonorrhea.

KC Huang, a microbiology and immunology bioengineer Stanford professor who is not part of the new research said that 'This compound is already so useful by itself, but also, people can start designing new compounds that are inspired by this. That's what has made this work so exciting.' The poisoned arrow dual mechanism can revolutionize antibiotic development. 'A study like this says that we can go back and revisit what we thought were the limitations on our development of new antibiotics,' said Huang

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